2-[alpha-(haloalkyl) benzylthio] imidazolines and tetrahydropyrimidines corresponding



United States Patent 6 2-[a-(HALOALKYL)BENZYL'IHIO]IMIDAZOLINES ANDTETRAHYDROPYRIMIDINES CORRE- SPON DING Robert C. Tweit, Wilmette, lll.,assignor to G. D. Searle & Co., Chicago, 111., a corporation of DelawareNo Drawing. Filed Aug. 11, 1959, Ser. No. 832,917 5 Claims. (Cl.260-251) -The present invention relates to novel derivatives of cyclicthioureas and, more particularly, to substituted haloalkylthio-dibasicnitrogen heterocycles of the structural formula wherein Alk is a loweralkylene radical, X is a halogen having an atomic weight greater than20, and n is a positive integer greater than one and less than 4. Thelower alkylene radicals represented by Alk are exemplified by:

(methylene) -CH:|CH3- (ethylene) -CHzCHzCHz- (trimethylene) CH3 -CH2C)H(1,2-propylene) -CH2CH2CH2CHz (tetramethylene) (methylmethylene)CHQCH2CHZ (propylmethylene) (lsopropylmethylene) CH3 J JHQCH3(methylethylmethylene) Suitable starting materials for the manufactureof the instant compounds are aralkyl dihalides in which one of thehalogen atoms is substituted on the carbon adjacent to the aromaticring. These dihalides are reacted with the appropriate cyclic thiourea,as shown below:

In the practice of this invention, it has been determined that selectivereaction occurs at the site of the benzyl halide halogen, i.e. at thecarbon adjacent to the phenyl ring, making possible facile iso.ation ofthe desired haloalkyl compounds in a high state of purity. As shownabove, the instant compounds are isolated in the form of theirhydrohalide salts. Other non-toxic salts which are equivalent for thepurpose of this invention are, for example, the citrate, maleate,tartrate, sulfate, etc.

The process disclosed supra is preferably conducted in the presence of asuitable ionic so.vent, typically a lower alkanol such as methanol, at atemperature approximating the boiling point of the solvent. After thereaction period has been completed, the product is isolated as thehydrohalide salt by precipitation from the reaction mixture. These saltsare converted to the corresponding free bases by alkalization with aninorganic alkali such as sodium carbonate, extraction into a suitableorganic solvent such as ether, and isolation by evaporation of thesolvent.

As a specific example of the instant process, (1,2-dib-romoethyl)benzeneis reacted with trimethylene thiourea in methanol at the refluxtemperature, to afford 2-[(2- bromo 1phenyl)ethylthio]tetrahydropyrimidine hydrobromide. Treatment of thissalt with excess sodium carbonate results in the free base,2-[(2-bromo-1-phenyl) ethylthio] tetrahydropyrimidine.

The compounds of this invention are useful as a result of their valuablepharmacological properties. They have the capacity, for example, toinhibit the local edema formation associated with inflammatory states.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein, as manymodifications in materials and methods will be apparent from thisdisclosure to those skilied in the art. In these examples, temperaturesare given in degrees centigrade C.). Quantities of materials areexpressed in parts by weight except where otherwise noted.

Example 1 Example 2 A mixture of 13.2 parts of(1,2-dibromoethyl)-benzene, 5.1 parts of ethylenethiourea, and" parts ofmethanol is heated on the steam bath until solution is complete, thenfiltered through diatomaceous earth and concentrated. Butanone is added,the small amount of precipitate removed by filtration, and the filtratediluted with ether and acetone. The solid which forms is re crystallizedfrom methanol-butanone to yield pure 2- [(2 bromo l phenyl)ethylthio]imidaz'oline hydrobromide, M.P. 159161.

By substituting an equivalent quantity of (1- bromo-3chloro-n-propyl)benzene and otherwise proceeding according to the hereindescribed processes, 2-[(3-chlorol-phenyI)-n-propylthio]imidazolinehydrobromide is obtaincd.

Example 3 A mixture of 5 parts of2-[(2-bromo-1-phenyl)-ethylthioJimidazoline hydrobromide, 10 parts ofsodium carbonate, 100 parts of water and 100 parts of ether is stirredfor about 30 minutes. The ether solution is separated, washed withwater, dried over anhydrous sodium sulfate, and concentrated to drynessto afford the oily free base,2-[(2-brorno-1-phenyl)ethy1thio1-imidazoline.

What is claimed is:

1. A member selected from the group of compounds of the structuralformula Alli-X and non-toxic salts thereof; wherein Alk is a loweralkylene radical, X is a halogen having an atomic weight greater than20, and n is a positive integer greater than one and less than 4.

2. A compound of the structural formula wherein Alk is a lower alkyleneradical and X is a halogen having an atomic Weight greater than 20. 3. Acompound of the structural formula cg, WLH

CHE-N H 20 pyrimidine.

No references cited.

1. A MEMBER SELECTED FROM THE GROUP OF CON OF THE STRUCTURAL FORMULA